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Activity and Risk Profile of Ponatinib in Chronic Phase Patients With Chronic Myeloid Leukemia Resistant to Imatinib

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ClinicalTrials.gov Identifier: NCT02398825
Recruitment Status : Unknown
Verified October 2017 by Gruppo Italiano Malattie EMatologiche dell'Adulto.
Recruitment status was:  Recruiting
First Posted : March 26, 2015
Last Update Posted : October 12, 2017
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

Study Description
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Brief Summary:
This study aims at evaluating the efficacy of treatment with ponatinib in patients with chronic myeloid leukemia who are in a chronic phase and who previously received treatment with imatinib but resulted to be resistant to it.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia Chronic Phase Adults Drug: Ponatinib Phase 2

Detailed Description:
Phase 2, single-arm, multicentre, open label. No interim analysis is planned, but a monitoring committee will evaluate the data every 6 months. Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level smaller or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol. Treatment time will be 52 weeks, during which study drug will be provided free-of-charge by ARIAD Pharmaceuticals, upon approval of the protocol. Treatment is discontinued at any time in case of failure or treatment-related SAEs. After one year of treatment, upon request of the local investigator and upon confirmation of the Treatment Advisory Committee (TAC, see section 23), ARIAD Pharmaceutics, Inc. will continue to provide ponatinib for the study patients who will benefit from treatment continuation, for at least 2 years, until the drug will be approved with that indication.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimizing Ponatinib USe (OPUS). A GIMEMA Phase 2 Study of the Activity and Risk Profile of Ponatinib, 30 mg Once Daily, in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients Resistant to Imatinib
Actual Study Start Date : August 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Ponatinib Drug: Ponatinib
Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level minor or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol.


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients with major cytogenetic response [ Time Frame: After 52 weeks of ponatinib treatment start ]

    Cytogenetic response (CyR) is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases:

    1. Major Cytogenetic Response if Ph pos metaphases < 35%
    2. Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1%
    3. Partial (PCyR) if Ph pos metaphases 1-34%
    4. Minor (mCyR) if Ph pos metaphases 35-65%
    5. Minimal or none (min/none CyR) if Ph pos metaphases > 65% If marrow cell metaphases cannot be obtained or analysed, interphase fluorescence-in-situ-hybridization (FISH) can be used, but only to distinguish a CCyR (minor or equal to 1% positive nuclei out of at least 200 nuclei) from a non CCyR. FISH data cannot be used to classify a response as minimal, minor, or partial.


Secondary Outcome Measures :
  1. Number of Cardiovascular Adverse Events (AEs) [ Time Frame: After three years from ponatinib treatment start ]
  2. Number of blood hypertension AEs [ Time Frame: After three years from ponatinib treatment start ]
  3. Number of pancreatitis AEs [ Time Frame: After three years from ponatinib treatment start ]
  4. Number of patients achieving Complete Cytogenetic Response (CCyR) [ Time Frame: After 52 weeks of ponatinib treatment start ]
  5. Number of patients achieving major molecular response [ Time Frame: After 52 weeks of ponatinib treatment start ]
  6. Number of patients with failure-free survival [ Time Frame: At 36 months from ponatinib treatment start ]
  7. Number of patients with progression-free survival [ Time Frame: At 36 months from ponatinib treatment start ]
  8. Number of patients in overal survival [ Time Frame: At 36 months from ponatinib treatment start ]
  9. Number of patients in event-free survival [ Time Frame: At 36 months from ponatinib treatment start ]
  10. Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires [ Time Frame: At baseline and at at weeks 4, 12, 24, 36 and 52 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML
  2. Age ≥ 18 years
  3. Chronic phase CML
  4. Prior treatment with imatinib, any dose

  5. Resistance to imatinib, as defined by any one of the ELN 2013 failure criteria, as follows:

    • no complete hematologic response (CHR) at 3 months
    • no cytogenetic response (CyR) (Ph+ > 95%) at 3 months
    • Less than partial CyR (PCyR, Ph+ > 35%) at 6 months
    • BCR-ABL1 > 10% at 6 months
    • Non complete CyR (CCyR) (Ph+ > 0%) at 12 months
    • BCR-ABL1 > 1% at 12 months
    • Loss of CHR, at any time
    • Loss of CCyR, at any time
    • Confirmed loss of major molecular response (MMR) (BCR-ABL1 bigger or equal to 0.1% in two consecutive tests, of which one bigger or equal to 1%), at any time
    • Any new BCR-ABL1 mutation, at any time
  6. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment
  7. An effective form of contraception with their sexual partners from enrolment through 4 months after the end of treatment
  8. Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures
  9. Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

  1. Accelerated or blastic phase CML
  2. Patients previously treated with nilotinib or dasatinib
  3. Patients with the T315I mutation
  4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse
  5. Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD)
  6. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation
  7. Pregnant or breastfeeding
  8. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
  9. Lack of informed consent
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02398825


Contacts
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Contact: Paola Fazi p.fazi@gimema.it
Contact: Enrico Crea e.crea@gimema.it

Locations
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Italy
Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi Recruiting
Ancona, Italy
Contact: Serena Rupoli         
Principal Investigator: Serena Rupoli         
Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi Recruiting
Bologna, Italy, 40138
Contact: Gianantonio Rosti, Dr.         
Principal Investigator: Gianantonio Rosti, Dr.         
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto" Recruiting
Catania, Italy
Contact: Fabio Stagno         
Principal Investigator: Fabio Stagno         
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano Recruiting
Milano, Italy
Contact: Alessandro Iurlo         
Principal Investigator: Alessandro Iurlo         
Milano Unità Trapianto di Midollo Ist. Nazionale Tumori Recruiting
Milano, Italy
Contact: Francesco Spina         
Principal Investigator: Francesco Spina         
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto Recruiting
Piacenza, Italy
Contact: Daniele Vallisa         
Principal Investigator: Daniele Vallisa         
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
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Study Chair: Gianantonio Rosti Department of Hematology, Oncology and Laboratory Medicine, S. Orsola-Malpighi University Hospital, Bologna
More Information
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT02398825    
Other Study ID Numbers: CML1315
2015-001102-34 ( EudraCT Number )
First Posted: March 26, 2015    Key Record Dates
Last Update Posted: October 12, 2017
Last Verified: October 2017
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Chronic myeloid leukemia
Chronic phase
Adults
Ponatinib
Imatinib resistant
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
 Hematologic Diseases
Ponatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action